Anthelmintic method employing certain dithiocarbanilates

ABSTRACT

Nemathelminthes and Platyhelminthes are controlled by exposing said helminthes to an effective amount of a compound of the formula   WHEREIN Z is selected from the group consisting of carboxy alkyl of not more than eight carbon atoms, furfuryl and -ACOOR wherein A is -CH2-, -CH2-CH2- or AND R is alkyl of not more than 18 carbon atoms; X is chloride, bromide or nitro and n is an integer from 0 to 5 inclusive provided that when X is nitro n is 1.

United States Patent 1 3,686,413

Hollrah [4 1 Aug. 22, 1972 [54] ANTHELMINTIC METHOD PrimaryEiraminerAlbert T. Meyers ENIPLOYING CERTAIN Assistant Examiner-VincentD. Turner DITHIOCARBANILATES Attorney-Paul C. Krizov, Neal E. Willis andRobert [72 Inventor: Glennon H. Hollrah, St. Louis, Mo. Gnesbauer [73]Assignee: Monsanto Company, St. Louis, Mo. [57] ABSTRACT [22] Filed:Dec. 22, 1969 Nemathelminthes and Platyhelminthes are controlled byexposing said helminthes to an effective amount of [211 App! 887406 acompound of the formula Related US. Application Data [63]Continuation-in-part of Ser. No. 523,582, Jan. X H s 28, 1966,abandoned, which is a continuationin-part of Ser. Nos. 440,003, March15, 1965, gzg h March wherein Z is selected from the group consisting ofcar- 1 aban one boxy alkyl of not more than eight carbon atoms, fur- 52us. Cl ..424/300, 424/285 ACOOR A CH2 [51] Int. Cl. ..A0ln 9/12, A0ln9/20, A61k 27/00 2 [58] Field of Search ..424/ 300, 285; 260/455 om"CI-I [56] References Cited V M p 4 M m UNITED STATES PATENTS and R isalkyl of not more than 18 carbon atoms; X is chloride, bromide or nitroand n is an integer from 0 2,786,866 3/ 1957 Hook et al ..260/455 to 5inclusive provided that when X is nitro n is l. 3,202,572 8/1965 Werreset al. ..424/300 7 Claims, No Drawings ANTHELMINTIC METHOD EMPLOYINGCERTAIN DITIIIOCARBANILATES This application is a continuation-in-partof application Ser. No. 523,582, filed Jan. 28, 1966 now abandoned,which in turn is a continuation-in-part of applications Ser. No. 440,003and Ser. No. 440,004, both filed Mar. 15, 1965 now abandoned.

This invention relates to the control of parasitic worm life and moreparticularly to the control of parasitic worm life belonging to thephyla Nemathelminthes and Platyhelminthes.

Parasitic worms of the phylum Nemathelminthes, class Nematoda, are roundworms found in the digestive system of animals, in soil and in variousplant systems. Parasitic worms of the phylum Platyhelminthes, classesCistoda (tapeworms) and Trematoda (flukes), are flat worms found in thedigestive systems of animals. Illustrative Nemathelminthes (round worms)include Ascaris suilla, Cephacia oblavata and Haemonchus contortus.Illustrative Platyhelminthes (flat worms) include Hymenolepis nana.

The term animal as used herein and in the appended claims includes, forexample, ruminants such as deer, goats, camels, sheep and cattle,monogastrics such as swine, rabbits, dogs, cats and hamsters, poultrysuch as chickens, turkeys, geese, ducks, guinea fowl, pigeons andpheasants, birds such as parrots, canaries and parakeets, and the like.

In accordance with this invention a method is provided for the controlof helminthes selected from the group consisting of Nemathelminthes andPlatyhelminthes which comprises exposing said helminthes to an effectiveamount of one or more dithiocarbanilates of the formula wherein Z isselected from the group consisting of carboxyalkyl of not more thaneight carbon atoms, furfuryl and ACOOR wherein A is CH,, CH -CH and R isalkyl of not more than '18 carbon atoms; X is selected from the groupconsisting of chloride, bromide and nitro; and n is an integer from to 5inclusive, provided that when X is nitro n is 1. Preferred compounds arethose wherein Z is furfuryl or ACOOR. Particularly preferred compoundsare those wherein X is chloride, n is an integer from 0 to 2 and Z isfurfuryl or ACOOR wherein R is alkyl of not more than four carbon atoms.

The dithiocarbanilates of the above formula will be referred tohereinafter as anthelmintic agents.

The anthelmintic agents used in this invention are effective incontrolling parasitic round worm infestation in soil, plants andanimals, and parasitic flat worm infestation in animals. Theseanthelmintic agents are particularly useful in the control of parasiticworm life since they effectively control the parasites at each stage oftheir life cycles, for example eggs, larvae and adult worms, and atconcentrations not injurious to the host plant or animal. Furthermore,they give prolonged protection against the parasitic worms followinginitial application. Such persistence or residual effect in the hostinsures prolonged protection from post-treatment attacks by theparasitic worms. The anthelmintic agents effectively control animalparasitic worms in their natural environment as well as the soil phaseof their life cycle. Treating barnyards, chicken pens, stables and otherinfested areas destroys eggs and infestive larvae of many parasiteswhich infest animals.

The following representative anthelmintic agents are useful inaccordance with the present invention.

I furfuryl 3,4-dichlorodithiocarbanilate II2-carboxyethyldithiocarbanilate III 1,2-dicarboxyethyl3,4-dichlorodithiocarbanilate IV methoxycarbonylmethyl3,4-dichlorodithiocarbanilate V ethoxycarbonylmethyl3,4-dichlorodithiocarbanilate VI n-butoxycarbonylmethyldithiocarbanilate VII ethoxycarbonylmethyl p-bromodithiocarbanilate VIIImethoxycarbonylmethyl p-chlorodithiocarbanilate IX ethoxycarbonylmethyl3,4-dibromodithiocarbanilate X l(ethoxy carbonyl)ethyl3,4-dichlorodithiocarbanilate XI l(propoxycarbonyl)ethyl3,4-dichlorodithiocarbanilate XII octadecyloxycarbonylmethylp-chlorodithiocarbanilate XIII ethoxycarbonylethylp-chlorodithiocarbanilate XIV l(propoxycarbonyl)ethylp-chlorodithiocarbanilate XV 1(ethoxycarbonyl)ethylp-chlorodithiocarbanilate XVI l(ethoxycarbonyl)ethylp-nitrodithiocarbanilate 2,3,4,5,6-pen- EXAMPLE 1 An aqueous suspensionof the nematode Turbatrix 5 aceti was mixed with furfuryl3,4-dichlorodithiocar- EXAMPLE 2 The sheep nematode Trichostrongyluscolubnformis which is also known to infect rabbits and rodents wascultured and used to inoculate rats by oral intubation. The inoculationdose contained about 1,000 nematode larvae. Twelve days afterinoculation the rats were fed by oral intubation three quarters of theL.D. rate of furfuryl 3,4-dichlorodithiocarbanilate (Compound I). Therats were sacrificed and a post-mortem examination revealed thatsubstantially all of the parasitic nematodes had been destroyed whereasthe untreated rats were severely infected and were small in size andshowed other evidence of malnutrition.

EXAMPLE 3 Complete kill of the nematode Turbatrix aceti was observed inaqueous suspension with ppm. of Compounds III, IV, V, VI, VII, VIII, IX,XI, XIII, XV and XXVIII.

EXAMPLE 4 The procedure of Example 2 is repeated utilizingethoxycarbonylmethyl 3,4-dichlorodithiocarbanilate (Compound V) at therate of 500 mg/Kg of body weight. The post-mortem examination revealedthat practically all of the nematodes were killed in the treated ratswhereas the control animals were very severely infected.

EXAMPLE 5 In this example the anthelmintic efficiency of representativedithiocarbanilates was determined by the modified McMaster egg countingmethod as described by H. B. Whitlock et al., .I. Coun. Sci. Ind. Res.(Aust) 12, 50 (1939), and H. B. Whitlock, J. Coun. Sci. Ind. Res. (Aust)21, 177 (1948). Three sheep were infested with larvae of Haemonchuscontortus. The sheep faeces were examined at intervals for eggs ofHaemonchus contortus to insure that infestation had occurred. Two ofthese sheep were then dosed with the anthelmintic agent at a rate of 100mg/Kg of body weight. Anthelmintic efficiency was determined by countingthe number of eggs/gram of sheep faeces panned on each of seven daysfollowing treatment and then comparing the number of eggs/gram of faecesfrom the treated sheep to the number of eggs/gram of faeces from theuntreated sheep. Results and further details are given in Table I.

Approximately 400 grams of a sandy loam soil inv room temperature. Thesoil is then potted and allowed to aerate for'7 days. Seedling tomatoplants (Improved Pearson are then transplanted in the aerated pottedsoil. After 4 weeks the plants are removed. Examination thereof showedno root-knot nematode galls on the treated plants. In contrast thecontrol plants averaged 66 root-knot nematode galls per plant.

EXAMPLE 7 Following the procedure of Example 6 and using an equal amountof furfuryl 3,4-dichlorodithiocarbanilate in place ofethoxycarbonylmethyl 3,4- dichlorodithiocarbanilate the treated plantswere found to average only 15 root-knot nematode galls in comparison to66 galls for the control plants.

EXAMPLE 8 Sufficient test compound is mixed with approximately 1,500grams of sandy loam soil to provide an'admixture containing 10 ppm ofthe test compound. The soil is potted in five 3 inch clay pots andSaticoy squash is planted in each pot using one seedling and one seedper pot. A nematode. suspension, Meloidogyne incognita acrita, isinjected around the root system and the plants are maintained under goodgrowth conditions for approximately 21 days. The galling on the roots ofthe test plants are compared with that of control plants potted underthe same conditions in soil free of the test compound. Using this testprocedure the galling on the EXAMPLE 9 The procedure of Example 8 isrepeated using soil containing 1 ppm of Compounds XIII, XIV, XV, XIX, XXand XXI. The galling on the roots of the test plants was reduced morethan percent when compared with that of the control plants.

In accordance with the method of this invention the anthelmintic agentscan be used alone or in combination with one or more solid or liquidadjuvants including diluents, extenders, carriers and conditioningagents to provide compositions in the form of particulate solids,granules, pellets, solutions, dispersions or emulsions. Typical solid orliquid adjuvants include, for example, particulate solids, solventliquids of organic origin, water, wetting agents, dispersing agents,emulsifying agents or any suitable combination of these.

In the treatment of Nemathelminthes in soil and plant systems inaccordance with this invention, the anthelmintic agents are preferablyapplied as granules with a conventional fertilizer spreader, asemulsifiable concentrate or wettable powder with a sprayer, or as a dustwith a conventional duster, or they can be absorbed in activated carbonfor application to seeds.

Veterinary application of anthelmintic agents in accordance with thisinvention for the treatment of Nemathelminthes and Platyhelminthes inanimals can i .be carried out by administering the anthelmintic agentsto the animals in the form of a liquid drench, suitably formulatedtablets or capsules, or animal feed compositions. The anthelminticagents can be incorporated into any of the general types of feed rationsconventionally fed to animals, e.g., dry laboratory chow diets; moist,semi-solid diets; relatively dry grain forage mixtures, and the like aswell as in the drinking water taken in by the animal to be treated. inthe treatment of animal parasitic worms the anthelmintic agents arepreferably administered orally as a liquid drench or tablet or capsulein unit dosage form. Alternatively, the anthelmintic agents can beincorporated into urea or salt licks or blocks.

The anthelmintic agents are usually applied to soil in the treatment ofNemathelminthes at a rate from about 0.001 to about 100 pounds per acre.Veterinary compositions for use in controlling parasitic infestations inanimals vary widely with respect to amount of anthelmintic agentdepending upon factors such as type of composition, type of host animalto be treated, the dose level desired and the severity and type ofparasitic infestation. Generally the anthelmintic agent is employed inan amount from about 5 mg/ Kg to about 500 or more mg/Kg of body weightof the treated animal.

The anthelmintic agents used in this invention also can be applied tothe parasitic infestations in admixture with other anthelmintics,medicaments, vitamin additive mixtures, and the like.

The dithiocarbanilates useful as anthelmintic agents in accordance withthis invention are prepared by various conventional methods, forexample, by reacting under mild conditions an arylisothiocyanate with amercaptan, such as furfuryl mercaptan, a mercaptoacid or an ester ofmercapto-acids such as methyl mercaptoacetate, isopropylmercaptoacetate, hexyl mercaptoacetate, dodecyl mercaptoacetate,octadecyl mercaptoacetate, ethyl a-mercaptopropionate, pentyla-mercaptopropionate, butyl ,B-mercaptopropionate, hexylB-mercaptopropionate and the like. Additionally, usefuldithiocarbanilates can be prepared by the reaction of aromatic amines,carbon disulfide and unsaturated acids and esters such as acrylic acid,crotonic acid, maleic acid, alkyl acrylates, alkyl crotonates,monoalkylmaleates, dialkylmaleates and the like in accordance with theprocedures more fully described in U.S. Pat. No. 2,786,866 to Edwin 0.Hook et al. Mar.

Although the invention is described with respect to specificmodifications, the details thereof are not to be construed aslimitations except to the extent indicated in the following claims.

The embodiments of the invention in which an exclusive property orprivilege is claimed are defined as follows:

1. A method of controlling Nemathelminthes in soil which comprisesapplying to said Nemathelminthes an effective anthelmintic amount of acompound of the formula wherein Z is selected from the group consistingof carboxyalkyl of not more than eight carbon atoms, furfuryl, and ACOORwherein A is selected from the group consisting of CH CH CH and and R isalkyl of not more than 18 carbon atoms; X is selected from the groupconsisting of chloride, bromide and nitro; and n is an integer from 0 to5, provided that when X is nitro n is 1.

2. A method in accordance with claim 1 wherein the compound isdodecyloxycarbonylmethyldithiocarbani late.

3. A method in accordance with claim 1 wherein the compound isdodecyloxycarbonylmethyl pchlorodithiocarbanilate.

4. A method in accordance with claim 1 wherein the compound isisopropoxycarbonylmethyldithiocarbani late.

5. A method in accordance with claim 1 wherein the compound isisopropoxycarbonylmethyl pchlorodithiocarbanilate.

6. A method in accordance with claim 1 wherein Z is ACOOR.

7. A method in accordance with claim 6 wherein R is alkyl of not morethan four carbon atoms, X is chloride and n is an integer from 0 to 2inclusive.

2. A method in accordance with claim 1 wherein the compound isdodecyloxycarbonylmethyldithiocarbanilate.
 3. A method in accordancewith claim 1 wherein the compound is dodecyloxycarbonylmethylp-chlorodithiocarbanilate.
 4. A method in accordance with claim 1wherein the compound is isopropoxycarbonylmethyldithiocarbanilate.
 5. Amethod in accordance with claim 1 wherein the compound isisopropoxycarbonylmethyl p-chlorodithiocarbanilate.
 6. A method inaccordance with claim 1 wherein Z is -ACOOR.
 7. A method in accordancewith claim 6 wherein R is alkyl of not more than four carbon atoms, X ischloride and n is an integer from 0 to 2 inclusive.